The present invention relates generally to the preservation of pharmaceutical compositions. In particular, the present invention relates to the use of certain anionic surfactants in combination with an antifungal acid and a chelating agent as a preservative system for topically administrable pharmaceutical compositions.
Multi-dose pharmaceutical products, particularly those intended for topical administration to the eyes, nose or ears, often contain or are required to contain a preservative. Such products are sterilized when manufactured, but contain preservatives to prevent or inhibit microbial growth in the event they are contaminated during use. The most common preservatives for topical, multi-dose ophthalmic products are quaternary ammonium preservatives, such as benzalkonium chloride and polyquaternium-1. Other known preservatives for topical, multi-dose ophthalmic products are chlorobutanol; chlorhexidine; parabens; and thimerosal (though thimerosal is not as common as it used to be, due to regulatory and environmental concerns related to the fact it contains mercury).
In some instances, preservatives alone are insufficient to meet regulatory standards for preservative efficacy. In such cases, preservative aids or adjuncts are used. Examples of preservative enhancing additives include the chelating agent EDTA (edetate disodium) and the antifungal agent boric acid. Additional examples of preservative enhancing additives include certain sarcosinate and lactylate surfactants.
U.S. Pat. No. 5,520,920 (Castillo, et al.) discloses the use of certain modified sarcosinates and lactylates to enhance antimicrobial effectiveness of ophthalmic compositions, particularly in the case where cationic preservatives otherwise bind to anionic polyelectrolytes. Representative modified sarcosinates include those sold under the Hamposyl.RTM. trade name, such as lauroyl sarcosine (Hamposyl.RTM. L), oleoyl sarcosine (Hamposyl.RTM. O), myristoyl sarcosine (Hamposyl.RTM. M), cocoyl sarcosine (Hamposyl.RTM. C), stearoyl sarcosine (Hamposyl.RTM. S), and pelargodoyl sarcosine (Hamposyl.RTM. P). Representative lactylates include sodium capryl lactylate (Pationic.RTM. 122A).
Anionic amino acid based surfactants other than the Hamposyl.RTM. surfactants are known and include, for example, those surfactants sold under the Amilite.TM. and Amisoft.TM. trade names (Ajinomoto Co., Inc., Tokyo, Japan). According to its product brochure, one such surfactant, Amilite.TM. GCK-12, is used as a detergent, a foaming agent, an emulsifier, a solubilizer and a dispersing agent. Examples of applications of Amilite.TM. GCK-12 include cosmetics and toiletries (hair shampoo and body wash), face wash (facial washing foam, facial washing creme, facial washing liquid and make-up remover), facial soap, toothpaste, bath soap, contact lens cleaners and household cleaners. Amisoft.TM. surfactants are described as gentle cleansers for the skin and hair. Major applications of Amisoft.TM. surfactants include facial and body cleansers, hair shampoos, syndet bars, body care and dermatological products.
Alternative preservative systems for topically administrable pharmaceutical compositions are desired, especially in those instances when conventional preservatives, such as benzalkonium chloride, are incompatible with other ingredients in the composition.